In U.S. Pat. No. 4,654,362 there are described 2,2xe2x80x2-iminobisethanol derivatives having xcex2 adrenergic blocking properties. It now has been found that a certain class of isomers of said bisethanol derivatives potentiate the activity of blood pressure reducing agents.
The present invention is concerned with a group of compounds capable of potentiating the effects of blood pressure reducing agents, said compounds being represented by the formula 
or the pharmaceutically acceptable acid addition salts thereof, wherein
R1 and R2 each independently are hydrogen or C1-6alkyl;
R3, R4, R5, R6, R7, R8, R9 and R10 each independently are hydrogen, halo, C1-6alkyl, C1-6alkyloxy, hydroxy, cyano, carboxy or C1-6alkyloxycarbonyl; or two vicinal radicals of R3, R4, R5, R6, R7, R8, R9 and R10 taken together may form a xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94(CH2)4xe2x80x94 radical.
As used in the foregoing definitions the term halo is generic to fluoro, chloro, bromo and iodo; the term xe2x80x9cC1-6alkylxe2x80x9d defines straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and the like.
The descriptors R and S as used in the above formula (I) indicate the absolute configuration at the respective carbon atoms. The carbon atom bearing R1 has the R configuration, whereas the carbon atoms bearing the hydroxy functions and the carbon atoms bearing R2 have the S configuration.
Preferred compounds of formula (I) are those wherein R3, R4, R6, R7, R8, and R10 are hydrogen.
Particularly preferred are those preferred compounds wherein R5 and R9 are hydrogen or halo, particularly fluoro.
The most preferred compound is [2R,xcex1S,2xe2x80x2S,xcex1S]-xcex1,xcex1xe2x80x2-[iminobismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or a pharmaceutically acceptable acid addition salt thereof.
The compounds of formula (I) can be prepared following the procedures described in U.S. Pat. No. 4,654,362. Some particular ways of obtaining the compounds of formula (I) will be described hereinafter in some more detail.
The compounds of formula (I) can be prepared by reacting an oxirane of formula (II-a) or (II-b) with an amine of formula (III-a) or (III-b). 
In (III-a) and (III-b), P is either hydrogen or an appropriate protecting group, for example an allyl group, or in particular P may be a benzyl group. Or, a reagent Pxe2x80x94NH2 may be reacted with (II-a) and (II-b) in a one-pot procedure. The above described reactions to prepare a compound of formula (I) may be conducted in a reaction-inert solvent such as, for example, an aromatic hydrocarbon, e.g. benzene or methylbenzene; an alkanol, e.g. methanol, ethanol, propanol; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone; an ether, e.g. 1,4-dioxane, tetrahydrofuran, 1,1xe2x80x2-oxybisethane; a dipolar aprotic solvent, e.g. N,N-dimethylformamide or N,N-dimethylacetamide and the like solvents. In certain instances, in order to increase the reaction rate, it may be appropriate to heat the reaction mixture.
If in the above reactions P is other than hydrogen, the N-protected derivatives of formula (I) are obtained wherefrom the compounds of formula (I) themselves can be obtained by a deprotection reaction. For example, where P is allyl, by reaction with an appropriate noble metal compound such as PdCl2 or Rh[P(C6H5)3]Cl, or where P is benzyl, by a catalytic hydrogenation procedure, e.g. palladium or platinum on charcoal in a suitable solvent such as an ether, e.g. 1,4-dioxane, tetrahydrofuran, an alkanol, e.g. methanol, ethanol, an alkoxyalkanol, e.g. methoxyethanol and the like.
The intermediates of formula (II-a) or (III-b) are obtained by the reaction of the amine P-KH2 with (II-b) or (II-a) or, by reacting a reagent P2NH, for example dibenzylamine, with (II-b) or (II-a) and subsequently selectively removing one of the P-groups, e.g. when P is benzyl by a catalytic hydrogenation procedure using one equivalent hydrogen. The afore described reactions to prepare (III-a) or (III-b) are conducted following the same procedures as described hereinabove for the preparation of the compounds (I).
The starting materials (II-a) are obtained by an oxirane formation reaction from an aldehyde of formula (IV-a), e.g. by reaction of the latter with a trimethylsulfoxonium halide, or from an ethylene of formula (V-a) by reaction of the latter with a peroxide, e.g. a haloperbenzoic acid. In the same way, the intermediate (II-b) is obtained from the corresponding S-isomers (IV-b) or (V-b). The oxiranes of formula (IV-a-1) obtained in the aforementioned oxirane-formation reaction are separated in their stereoisomers, e.g. by HPLC or selective crystallization. 
The compounds of formula (IV-a), (IV-b), (V-a) or (V-b) are obtained by a suitable separation procedure, i.e. by HPLC, or by a reduction reaction of the corresponding optically active racemic acids whereas (IV-a) or (IV-b) can be converted to (V-a) or (V-b) by a Wittig reaction. The said corresponding optically active acids in turn can be obtained by conventional separation techniques, i.e. by salt or amide formation with an optically active reagent and a selective crystallization procedure or a HPLC separation.
The compounds of formula (I) have basic properties and, consequently, they may be converted to their therapeutically active non-toxic acid addition salt forms by treatment with appropriate acids, such as, for example, inorganic acids, such as hydrohalic acid, e.g. hydrochloric, hydrobromic and the like, and sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids, such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propane-tricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
Conversely, the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) with the exception of (RSSS)-xcex1,xcex1xe2x80x2-[iminobis(methylene)bis(3,4-dihydro-2H-1-benzopyran-2-methanol] ethanedioate(1:1) are deemed to be novel compounds and constitute in an additional feature to the present invention.
The compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof potentiate the activity of blood pressure reducing agents. In particular they potentiate the reduction of the blood pressure and of the heart rate.
As blood pressure reducing agents of which the activity is potentiated there may be mentioned agents having adrenergic and/or vasodilating activity. In particular such agents may be the compounds mentioned in U.S. Pat. Nos. 3,663,607 and 3,836,671, in particular atenolol; U.S. Pat. Nos. 3,337,628 and 3,520,919, in particular propranolol; U.S. Pat. No. 3,873,600, in particular metoprolol; U.S. Pat. No. 3,511,836, in particular prazosin; U.S. Pat. No. 2,484,029, in particular hydralazine; U.S. Pat. No. 2,928,829 in particular guanethidine; U.S. Pat. No. 2,503,059, in particular phentolamine; U.S. Pat. No. 3,261,859, in particular verapamil; U.S. Pat. No. 3,485,847 in particular nifedipine; U.S. Pat. No. 3,910,924, in particular carteolol; German Pat. Nos. 2,458,624 and 2,458,625, in particular celiprolol. A particular group of blood pressure reducing compounds are the compounds of U.S. Pat. No. 4,654,362 other than the compounds of formula (I) and in particular the enantiomers of the compounds of formula (I), i.e. the SRRR-isomers. A particular compound is [2S,xcex1R,2xe2x80x2R,xcex1xe2x80x2R]-xcex1,xcex1xe2x80x2-[iminobismethylene]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol. These groups of active ingredients are listed with the purpose of providing representative examples but not with the purpose of restricting the scope of the present invention. The said SRRR isomers and the said particular compound can be prepared following the same procedures as previously described for the preparation of the compounds of formula (I), but starting from the enantiomers of the intermediates (II-a), (III-a), (II-b) and (III-b). The latter enantiomers in turn can be obtained as described hereinabove for the preparation of (II-a), (III-a), (II-b) and (III-b), but starting from the enantiomers of (IV-a) or (V-a) and isolating the appropriate stereoisomers in stereochemical separation procedures. The enantiomers of (IV-a) and (V-a) in the same way can be obtained as described for the preparation of (IV-a) and (V-a) starting from the appropriate enantiomeric starting materials and/or isolating the appropriate stereoisomers in stereochemical separations.
The compounds of formula (I) and the acid addition salts thereof may be administered before, during or after the administration of the blood pressure reducing agent provided that the time of the administration of the compounds of formula (I) in relation to the administration of the blood pressure reducing agent allows the compound of formula (I) to be effective in potentiating the effects of the blood pressure reducing agent. Preferably the compound of formula (I) and the blood pressure reducing agent are administered in the form of suitable compositions. Said compositions are meant to also comprise products containing a compound of formula (I) as defined hereinabove and a blood-pressure reducing agent as a combined preparation for simultaneous, separate or sequential use in blood-pressure reducing therapy. Such products may for example comprise a kit comprising a container with a suitable composition containing a compound of formula (I) and another container containing a composition with a blood pressure reducing agent. Such product may have the advantage that the physician wishing to administer blood pressure reducing therapy can select, based on the diagnosis of the patient to be treated, the appropriate amounts of both components and the sequence of administration.
When administered during the administration of the blood pressure reducing agent, a composition containing both the blood pressure reducing agent and the active ingredient of formula (I) may particularly be convenient.
In a further aspect of the present invention there is provided a composition comprising an amount capable of potentiating the effects of blood pressure reducing agents of a compound of formula (I) as defined hereinabove and a blood pressure reducing agent. In the said composition, the molar ratio between the compound of formula (I) and the blood pressure reducing agent may be other than 1:1, but in particular may be 1:1. The amount of the active ingredient of formula (I) in such composition will be so that a potentiating effect on the effects of the blood-pressure reducing agent is obtained; the amount of the blood pressure reducing agent will be so that when potentiated, a blood pressure reducing effect is obtained upon administration. In particular, it is contemplated that the molar ratio of the compound of formula (I) to the blood pressure reducing compound may be situated between 50:1 and 1:50, in particular between 20:1 and 1:20, or between 10:1 and 1:10, or between 5:1 and 1:5, more particularly between 2:1 and 1:2. Particular such compositions are those wherein the blood pressure reducing agent is one of the agents pertaining to the patents cited hereinabove, and more particularly the agents specifically mentioned hereinabove.
The present invention also provides a composition comprising a pharmaceutically acceptable carrier and as active ingredient an amount capable of potentiating the effects of blood pressure reducing agents of a novel compound of formula (I) or a pharmaceutically acceptable acid-addition salt thereof, as defined hereinabove.
To prepare such pharmaceutical compositions, an effective amount of the particular compound or compounds, in base or acid-addition salt form, as the active ingredient or active ingredients is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deletorious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid addition salts of (I) due to their increased water solubility over the corresponding base form, are obviously more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
The present invention also concerns a method of potentiating the effects of blood pressure reducing agents in warm-blooded animals in need of blood pressure reducing medication, said method comprising administering to said warm-blooded animals of an effective amount of a blood pressure reducing agent and a compound of formula (I) as defined hereinabove.
Or alternatively, the present invention concerns a method of lowering the blood pressure in warm-blooded animals suffering therefrom, said method comprising administering to said warm-blooded animals of an effective amount of a blood pressure reducing agent and a compound of formula (I) as defined hereinabove.
Those of skill in treating subjects suffering from an increased blood pressure could easily determine the effective amount from the test results presented hereinafter. In general it is contemplated that an effective daily dose of the compounds of formula (I) or their pharmaceutically acceptable acid-addition salts would be from 0.01 mg/kg to 50 mg/kg body weight, in particular from 0.1 mg/kg to 10 mg/kg body weight and preferably from 0.1 mg/kg to 1 mg/kg body weight.
All above cited references are incorporated herein by reference.